US4164495A - Method of recovering immunoglobulin using a polyol and an alkanoic acid - Google Patents

Method of recovering immunoglobulin using a polyol and an alkanoic acid Download PDF

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Publication number
US4164495A
US4164495A US05/914,456 US91445678A US4164495A US 4164495 A US4164495 A US 4164495A US 91445678 A US91445678 A US 91445678A US 4164495 A US4164495 A US 4164495A
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Prior art keywords
acid
polyol
alkanoic acid
precipitation
immunoglobulin
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US05/914,456
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Jorgen F. Hansen
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Nordisk Insulinlaboratorium
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Nordisk Insulinlaboratorium
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Priority claimed from DK162876AA external-priority patent/DK139056B/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/829—Blood
    • Y10S530/83—Plasma; serum

Definitions

  • the present invention relates to a method of recovering immunoglobulin suitable for intravenous administration, by fractionated precipitation of blood plasma, serum or a fraction thereof with a polycondensed di or polyol.
  • Immunoglobulins comprising gammaglobulins have therapeutic merit as they are suitable for preparing immunizing preparations.
  • Immunoglobulin is found in blood plasma of animal origin, from which it may be recovered by various precipitation and purification processes. Hence, gammaglobulin can be recovered as concentrated solutions by a method developed by Cohn et al, cf. J. Clin. Invest. Chem. Soc., 68, 479-75 (1946). According to Cohn, it is possible to obtain a fraction II being a 16.5% concentrate and which may be injected intramuscularly.
  • Cohn's method comprises precipitation with alcohol which has a water-expelling effect and may lead to irreversible denaturation, whereby the globulin is rendered anti-complementary. It has been attempted to avoid this by means of special separation processes and/or by chemical modification of the gammaglobulin.
  • the prior art teaches an improved fractionating process in which the gammaglobulin is precipitated from blood plasma by means of polyethylene glycol (PEG) as precipitant, cf. U.S. Pat. No. 3,415,804. This eliminates the undesired denaturation, but the purity of the precipated product is unsatisfactory.
  • PEG polyethylene glycol
  • this precipitation process may be improved by replacing polyethylene glycol by a block copolymer of ethylene oxide and polyoxypropylene polymer of a further specified nature and observing some specific precipitation conditions.
  • the present invention is based on the observation that the fractionated precipitation of immunoglobulins, also known as gammaglobulins, by means of polyethylene glycol or other polycondensed di or polyol may be rendered appreciably more specific if the precipitation is carried out in the presence of a mono or polyalkanoic acid having from 4 to 12 carbon atoms, whereby i.a. fibrinogen and lipoproteins are removed.
  • the claimed method may be used in connection with any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, preferably 4000 to 6000, or polypropylene glycol. Also copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
  • polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, preferably 4000 to 6000, or polypropylene glycol.
  • copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
  • Suitable as mono or polyalkanoic acid is any alkanoic acid having from 4 to 12 carbon atoms.
  • Preferred according to the invention is an alkanoic acid having from 6 to 9 carbon atoms, preferably caprylic acid.
  • examples of other suitable alkanoic acids are caproic acid and nonanic acid.
  • branched alkanoic acids may be used.
  • higher alkanoic acids such as having from 9 to 12 carbon atoms, it may be advantageous to incorporate additionally one or more carboxyl groups with a view to improving water-solubility. The same effect is achieved by using alkanoic acids having substituents containing, for example, one or more hydroxyl groups or amino groups.
  • the immunoglobulin-containing solution is advantageously mixed with from 1 to 8 percent by weight of polyethylene glycol or other polycondensed diol or polyol together with from 0.1 to 5 percent by weight of caprylic acid or other alkanoic acid having from 4 to 12 carbon atoms, the precipitation with alkanoic acid according to the invention being advantageously effected at a pH of from 3 to 7, preferably from 4.5 to 5.5.
  • the solution is filtered until clear using a Seitz EK-filter.
  • the solution formed is admixed with 5 g of caprylic acid and 30 g of PEG 3000 per liter solution, and adjusted to a pH of 4.9. After leaving to stand for 2 hours at 20° C. the mixture is centrifugated, and the liquid phase is filtered to obtain a clear solution.
  • the yield of product is 60 percent.
  • the degree of purity as determined by DISC PAGE discloses substantially only two bands corresponding to IgG and IgM, respectively. The analysis is performed by application of 500 ⁇ g of product.
  • the purified product may, if desired, be converted to an intravenously injectable preparation by dissolution in 0.9 percent sodium chloride solution until a protein concentration of about 5 percent.
  • the preparation is distinguished by an extremely low anticomplementary activity, for which reason it is particularly suitable for intravenous administration.
  • Example 2 The procedure according to Example 1 is repeated, except that the human blood plasma is replaced by swine plasma.
  • Example 1 The procedure according to Example 1 is repeated, except that human blood plasma is replaced by blood serum.
  • 100 l of plasma or serum are mixed with 100 l of 600 g/l PEG 3000 solution.
  • the pH is adjusted to 6.5.
  • the precipitate is separated by centrifugation and redissolved in 100 l of distilled water admixed with 0.015 M of NaCl.
  • the pH is adjusted to 5.0.
  • the precipitate is separated by centrifugation.
  • the centrifugate is admixed with additional 40 g of PEG 3000 per liter.
  • the pH is adjusted to 7.5.
  • the precipitate is separated by centrifugation and redissolved in distilled water with 0.002 M of NaCl.
  • the solution is filtered to clarity (e.g. SEITZ ® EK-Filter).
  • the protein concentration should be 50-100 g/l.
  • 20 g of DEAE-Sephadex-A25 ® are added per 100 g of protein.
  • the DEAE-Sephadex is separated by filtration.
  • the DEAE-Sephadex treatment is repeated. After sterile filtration there is obtained an immunoglobulin G preparation free from anticomplementariness and suitable for intravenous administration.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Immunoglobulins or gammaglobulins are recovered in a pure and anticomplementary condition by fractionated precipitation of blood plasma with a polycondensed di or polyol, such as PEG, in the presence of a mono or polyalkanoic acid having 4 to 12 carbon atoms, such as caprylic acid.

Description

This is a continuation of application Ser. No. 782,255 filed Mar. 28, 1977 and now abandoned.
The present invention relates to a method of recovering immunoglobulin suitable for intravenous administration, by fractionated precipitation of blood plasma, serum or a fraction thereof with a polycondensed di or polyol.
Immunoglobulins comprising gammaglobulins have therapeutic merit as they are suitable for preparing immunizing preparations.
Immunoglobulin is found in blood plasma of animal origin, from which it may be recovered by various precipitation and purification processes. Hence, gammaglobulin can be recovered as concentrated solutions by a method developed by Cohn et al, cf. J. Clin. Invest. Chem. Soc., 68, 479-75 (1946). According to Cohn, it is possible to obtain a fraction II being a 16.5% concentrate and which may be injected intramuscularly.
In the said prior-art method there are formed molecule aggregates of gammaglobulin rendering the products unsuitable for intravenous administration. Hence, Cohn's method comprises precipitation with alcohol which has a water-expelling effect and may lead to irreversible denaturation, whereby the globulin is rendered anti-complementary. It has been attempted to avoid this by means of special separation processes and/or by chemical modification of the gammaglobulin.
Hence, the prior art teaches an improved fractionating process in which the gammaglobulin is precipitated from blood plasma by means of polyethylene glycol (PEG) as precipitant, cf. U.S. Pat. No. 3,415,804. This eliminates the undesired denaturation, but the purity of the precipated product is unsatisfactory.
According to Danish Patent Application No. 6355/73, this precipitation process may be improved by replacing polyethylene glycol by a block copolymer of ethylene oxide and polyoxypropylene polymer of a further specified nature and observing some specific precipitation conditions.
In this manner it is possible to improve the yield by recovery of gammaglobulin. The precipitated products, however, are not always of satisfactory purity with sufficiently low anticomplementary activity.
The present invention is based on the observation that the fractionated precipitation of immunoglobulins, also known as gammaglobulins, by means of polyethylene glycol or other polycondensed di or polyol may be rendered appreciably more specific if the precipitation is carried out in the presence of a mono or polyalkanoic acid having from 4 to 12 carbon atoms, whereby i.a. fibrinogen and lipoproteins are removed.
In the method according to the invention there is obtained in a simple manner purified immunoglobulin of a surprisingly high degree of purity coupled with a high yield. The yield equals that which it is possible to obtain by the best of the aforesaid methods.
The claimed method may be used in connection with any polycondensed di or polyglycol such as polyethylene glycol of varying molecular weights, e.g. 2000 to 12000, preferably 4000 to 6000, or polypropylene glycol. Also copolymers of ethylene oxide with propylene oxide or polyethers are suitable.
Suitable as mono or polyalkanoic acid is any alkanoic acid having from 4 to 12 carbon atoms. Preferred according to the invention is an alkanoic acid having from 6 to 9 carbon atoms, preferably caprylic acid. Examples of other suitable alkanoic acids are caproic acid and nonanic acid. Also branched alkanoic acids may be used. When using higher alkanoic acids, such as having from 9 to 12 carbon atoms, it may be advantageous to incorporate additionally one or more carboxyl groups with a view to improving water-solubility. The same effect is achieved by using alkanoic acids having substituents containing, for example, one or more hydroxyl groups or amino groups.
The immunoglobulin-containing solution is advantageously mixed with from 1 to 8 percent by weight of polyethylene glycol or other polycondensed diol or polyol together with from 0.1 to 5 percent by weight of caprylic acid or other alkanoic acid having from 4 to 12 carbon atoms, the precipitation with alkanoic acid according to the invention being advantageously effected at a pH of from 3 to 7, preferably from 4.5 to 5.5.
The method according to the invention will now be further illustrated below by means of some examples.
EXAMPLE 1
415 ml of human blood plasma containing 10 g of immunoglobulin per liter plasma are adjusted to a pH of 5.0 PEG 3000 is added until a concentration of 6 percent, and the solution is left to stand for 45 minutes. The precipitate, being mainly fibrinogen, is separated by centrifugation, and the liquid phase is adjusted to a pH of 7.0. After adding additional PEG 3000 to obtain a concentration of 12 percent, the mixture is left to stand for 45 minutes. The mixture is now centrifugated and the liquid phase containing albumin and alpha and beta-globulin is removed. The precipitate consisting of impure immunoglobulin is redissolved in an 0.9 percent sodium chloride solution to obtain a protein concentration of about 4 percent. The solution is filtered until clear using a Seitz EK-filter. The solution formed is admixed with 5 g of caprylic acid and 30 g of PEG 3000 per liter solution, and adjusted to a pH of 4.9. After leaving to stand for 2 hours at 20° C. the mixture is centrifugated, and the liquid phase is filtered to obtain a clear solution. This solution is adjusted to pH=7.0, and PEG 3000 is added until a concentration of 12 percent PEG. This results in precipitation of pure immunoglobulin which is recovered by centrifugation and drying. The yield of product is 60 percent. The degree of purity as determined by DISC PAGE (with 5 percent polyacrylamide) discloses substantially only two bands corresponding to IgG and IgM, respectively. The analysis is performed by application of 500 μg of product.
In Grabar and William's immunoelectrophoresis, using rabbit antibody against total human serum protein, there is found substantially only three arches, corresponding to IgG, IgM and IgA, respectively.
The purified product may, if desired, be converted to an intravenously injectable preparation by dissolution in 0.9 percent sodium chloride solution until a protein concentration of about 5 percent. The preparation is distinguished by an extremely low anticomplementary activity, for which reason it is particularly suitable for intravenous administration.
EXAMPLE 2
The procedure according to Example 1 is repeated, except that the human blood plasma is replaced by swine plasma.
EXAMPLE 3
The procedure according to Example 1 is repeated, except that human blood plasma is replaced by blood serum.
EXAMPLE 4
100 l of plasma or serum are mixed with 100 l of 600 g/l PEG 3000 solution. The pH is adjusted to 6.5. The precipitate is separated by centrifugation and redissolved in 100 l of distilled water admixed with 0.015 M of NaCl. There is added 40 g of PEG 3000 per liter and 5 g of caprylic acid per liter. The pH is adjusted to 5.0. Standing time 45 minutes. The precipitate is separated by centrifugation. The centrifugate is admixed with additional 40 g of PEG 3000 per liter. The pH is adjusted to 7.5. The precipitate is separated by centrifugation and redissolved in distilled water with 0.002 M of NaCl. The solution is filtered to clarity (e.g. SEITZ ® EK-Filter). The protein concentration should be 50-100 g/l. 20 g of DEAE-Sephadex-A25 ® are added per 100 g of protein. After leaving to stand for 60 minutes while stirring the DEAE-Sephadex is separated by filtration. The DEAE-Sephadex treatment is repeated. After sterile filtration there is obtained an immunoglobulin G preparation free from anticomplementariness and suitable for intravenous administration.

Claims (6)

What I claim is:
1. A method of recovering purified immunoglobulin suitable for intravenous administration wherein blood plasma, serum or a fraction thereof is subjected to a fractionated precipitation using a combination of polycondensed polyol and a mono or polyalkanoic acid having from 4 to 12 carbon atoms as a precipitant, the fractionating process being performed at approximately room temperature.
2. A method according to claim 1, characterized in that the mono or polyalkanoic acid is an alkanoic acid having from 6 to 9 carbon atoms.
3. A method according to claim 1 or claim 2, characterized by effecting the precipitation with alkanoic acid at a pH of from 3 to 7.
4. A process according to claim 1 wherein the polyol is a diol.
5. A method according to claim 3 wherein the pH is from 4.5 to 5.5.
6. A method according to claim 2 wherein the alkanoic acid is caprylic acid.
US05/914,456 1976-04-06 1978-06-12 Method of recovering immunoglobulin using a polyol and an alkanoic acid Expired - Lifetime US4164495A (en)

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DK162876AA DK139056B (en) 1976-04-06 1976-04-06 Method for recovering immunoglobulin suitable for intravenous administration.
DK1628/76 1976-04-06
US78225577A 1977-03-28 1977-03-28
US05/914,456 US4164495A (en) 1976-04-06 1978-06-12 Method of recovering immunoglobulin using a polyol and an alkanoic acid

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4296027A (en) * 1977-08-31 1981-10-20 The Regents Of The University Of Minnesota Pure intravenous human and animal gamma globulins
US4344938A (en) * 1978-10-25 1982-08-17 Behringwerke Aktiengesellschaft Agent for the treatment of allergic reactions
EP0078331A1 (en) * 1981-10-29 1983-05-11 Green Cross Corporation Process for preparing immunoglobulin suitable for intravenous injection
EP0092186A2 (en) * 1982-04-16 1983-10-26 FUJIREBIO KABUSHIKI KAISHA also trading as FUJIREBIO INC. Method of preparing gamma globulin suitable for intravenous administration
US4639513A (en) * 1984-02-02 1987-01-27 Cuno Inc. Intravenously injectable immunoglobulin G (IGG) and method for producing same
US5219578A (en) * 1991-02-25 1993-06-15 Innovet, Inc. Composition and method for immunostimulation in mammals
US5248767A (en) * 1986-06-11 1993-09-28 Behringwerke Aktiengesellschaft Process for the preparation of a pasteurized immunoglobulin preparation using ethanol
US5525519A (en) * 1992-01-07 1996-06-11 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
WO1997003092A1 (en) * 1995-07-13 1997-01-30 Hemasure A/S A process for removal of polyethylene glycol from a protein or peptide solution
US20020151688A1 (en) * 2001-01-17 2002-10-17 Probitas Pharma, S.A. Process for the production of virus-inactivated human gammaglobulin G
US20050272917A1 (en) * 2004-05-14 2005-12-08 Hematech, Llc Methods for immunoglobulin purification
US20060226086A1 (en) * 2005-04-08 2006-10-12 Robinson Thomas C Centrifuge for blood processing systems
US20090292109A1 (en) * 2008-04-16 2009-11-26 Biogen Idec Ma Inc. Method of Isolating Biomacromolecules Using Polyalkylene Glycol and Transition Metals
US20100145022A1 (en) * 2006-11-01 2010-06-10 Biogen Idic Ma Inc. Method of Isolating Biomacromolecules Using Low pH and Divalent Cations
WO2015056237A2 (en) 2013-10-18 2015-04-23 Universität Für Bodenkultur Wien Purification of proteins
US10358462B2 (en) * 2015-08-31 2019-07-23 Instituto Grifols, S.A. Method for the preparation of immunoglobulins
RU2708394C2 (en) * 2016-09-26 2019-12-06 Институто Грифольс,С.А. Method of producing immunoglobulins
AU2016231646B2 (en) * 2016-09-26 2021-04-08 Instituto Grifols, S.A. Method for the preparation of immunoglobulins

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US3100737A (en) * 1958-02-05 1963-08-13 Auerswald Wilhelm Method of preparing a plasma protein solution free of active hepatitis virus and product produced thereby
US3415804A (en) * 1962-01-03 1968-12-10 South African Inventions Fractionation of mixtures of proteinaceous substances using polyethylene glycol
US3686395A (en) * 1966-04-06 1972-08-22 Biotest Serum Institut Gmbh Process for preparation of storage stable hepatitis-free serum
US3770631A (en) * 1971-06-29 1973-11-06 Baxter Laboratories Inc Clarification of blood serum and plasma
US3869436A (en) * 1971-06-01 1975-03-04 Statens Bakteriologiska Lab Method for fractionating plasma proteins using peg and ion-exchangers
US3876775A (en) * 1972-06-19 1975-04-08 Cutter Lab Stable intravenously injectable plasma protein free from hypotensive effects and process for its production
US3880989A (en) * 1973-01-30 1975-04-29 Baxter Laboratories Inc Production of antisera comprising fractionating plasma or serum with an ethylene oxide-polyoxypropylene block copolymer
US3916026A (en) * 1968-09-19 1975-10-28 Biotest Serum Institut Gmbh Method for the preparation of gamma-globulin suitable for intravenous use
US4017470A (en) * 1974-02-18 1977-04-12 The Green Cross Corporation Method for preparing a heat-stable plasma protein solution from paste IV-1
US4021540A (en) * 1975-07-28 1977-05-03 Ortho Diagnostics Inc. Preparation of a hepatitis B immune globulin and use thereof as a prophylactic material
US4075193A (en) * 1976-11-26 1978-02-21 Parke, Davis & Company Process for producing intravenous immune globulin
US4082734A (en) * 1975-06-18 1978-04-04 Biotest-Serum-Institut Gmbh Production of intravenously applicable native human immune globulin having a normal half-life
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US3100737A (en) * 1958-02-05 1963-08-13 Auerswald Wilhelm Method of preparing a plasma protein solution free of active hepatitis virus and product produced thereby
US3415804A (en) * 1962-01-03 1968-12-10 South African Inventions Fractionation of mixtures of proteinaceous substances using polyethylene glycol
US3686395A (en) * 1966-04-06 1972-08-22 Biotest Serum Institut Gmbh Process for preparation of storage stable hepatitis-free serum
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US3770631A (en) * 1971-06-29 1973-11-06 Baxter Laboratories Inc Clarification of blood serum and plasma
US3876775A (en) * 1972-06-19 1975-04-08 Cutter Lab Stable intravenously injectable plasma protein free from hypotensive effects and process for its production
US3880989A (en) * 1973-01-30 1975-04-29 Baxter Laboratories Inc Production of antisera comprising fractionating plasma or serum with an ethylene oxide-polyoxypropylene block copolymer
US4017470A (en) * 1974-02-18 1977-04-12 The Green Cross Corporation Method for preparing a heat-stable plasma protein solution from paste IV-1
US4093606A (en) * 1975-02-18 1978-06-06 Coval M L Method of producing intravenously injectable gamma globulin and a gamma globulin suitable for carrying out the method
US4082734A (en) * 1975-06-18 1978-04-04 Biotest-Serum-Institut Gmbh Production of intravenously applicable native human immune globulin having a normal half-life
US4021540A (en) * 1975-07-28 1977-05-03 Ortho Diagnostics Inc. Preparation of a hepatitis B immune globulin and use thereof as a prophylactic material
US4075193A (en) * 1976-11-26 1978-02-21 Parke, Davis & Company Process for producing intravenous immune globulin

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4296027A (en) * 1977-08-31 1981-10-20 The Regents Of The University Of Minnesota Pure intravenous human and animal gamma globulins
US4344938A (en) * 1978-10-25 1982-08-17 Behringwerke Aktiengesellschaft Agent for the treatment of allergic reactions
EP0078331A1 (en) * 1981-10-29 1983-05-11 Green Cross Corporation Process for preparing immunoglobulin suitable for intravenous injection
EP0092186A2 (en) * 1982-04-16 1983-10-26 FUJIREBIO KABUSHIKI KAISHA also trading as FUJIREBIO INC. Method of preparing gamma globulin suitable for intravenous administration
EP0092186A3 (en) * 1982-04-16 1984-07-18 Fujirebio Kabushiki Kaisha Also Trading As Fujirebio Inc. Method of preparing gamma globulin suitable for intravenous administration
US4515776A (en) * 1982-04-16 1985-05-07 Fujirebio Kabushiki Kaisha Method of preparing gamma globulin suitable for intravenous administration
US4639513A (en) * 1984-02-02 1987-01-27 Cuno Inc. Intravenously injectable immunoglobulin G (IGG) and method for producing same
US5248767A (en) * 1986-06-11 1993-09-28 Behringwerke Aktiengesellschaft Process for the preparation of a pasteurized immunoglobulin preparation using ethanol
US5219578A (en) * 1991-02-25 1993-06-15 Innovet, Inc. Composition and method for immunostimulation in mammals
US5525519A (en) * 1992-01-07 1996-06-11 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
US5599719A (en) * 1992-01-07 1997-02-04 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
WO1997003092A1 (en) * 1995-07-13 1997-01-30 Hemasure A/S A process for removal of polyethylene glycol from a protein or peptide solution
US20020151688A1 (en) * 2001-01-17 2002-10-17 Probitas Pharma, S.A. Process for the production of virus-inactivated human gammaglobulin G
ES2184594A1 (en) * 2001-01-17 2003-04-01 Probitas Pharma Sa Process for the production of virus-inactivated human gammaglobulin G
US6875848B2 (en) 2001-01-17 2005-04-05 Probitas Pharma, S.A. Process for the production of virus-inactivated human gammaglobulin G
US20050272917A1 (en) * 2004-05-14 2005-12-08 Hematech, Llc Methods for immunoglobulin purification
US20060226086A1 (en) * 2005-04-08 2006-10-12 Robinson Thomas C Centrifuge for blood processing systems
US20100145022A1 (en) * 2006-11-01 2010-06-10 Biogen Idic Ma Inc. Method of Isolating Biomacromolecules Using Low pH and Divalent Cations
US9109015B2 (en) 2006-11-01 2015-08-18 Biogen Ma Inc Method of isolating biomacromolecules using low pH and divalent cations
US20090292109A1 (en) * 2008-04-16 2009-11-26 Biogen Idec Ma Inc. Method of Isolating Biomacromolecules Using Polyalkylene Glycol and Transition Metals
WO2015056237A2 (en) 2013-10-18 2015-04-23 Universität Für Bodenkultur Wien Purification of proteins
US10508133B2 (en) 2013-10-18 2019-12-17 Novasep Process Purification of proteins
US10358462B2 (en) * 2015-08-31 2019-07-23 Instituto Grifols, S.A. Method for the preparation of immunoglobulins
RU2708394C2 (en) * 2016-09-26 2019-12-06 Институто Грифольс,С.А. Method of producing immunoglobulins
AU2016231646B2 (en) * 2016-09-26 2021-04-08 Instituto Grifols, S.A. Method for the preparation of immunoglobulins

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